Volume 11, Number 6; 1481-1495, December 2020

http://dx.doi.org/10.14336/AD.2020.0903

Review

COVID-19 in Elderly Adults: Clinical Features,

Molecular Mechanisms, and Proposed Strategies
Ya Yang#, Yalei Zhao#, Fen Zhang, Lingjian Zhang, Lanjuan Li*

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for
Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The
First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
[Received July 5, 2020; Revised September 1, 2020; Accepted September 3, 2020]

ABSTRACT: Coronavirus disease 2019 (COVID-19) is causing problems worldwide. Most people are susceptible
to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but elderly populations are more susceptible.
Elevated susceptibility and death rates in elderly COVID-19 patients, especially those with age-related
complications, are challenges for pandemic prevention and control. In this paper, we review the clinical features
of elderly patients with COVID-19 and explore the related molecular mechanisms that are essential for the
exploration of preventive and therapeutic strategies in the current pandemic. Furthermore, we analyze the
feasibility of currently recommended potential novel methods against COVID-19 among elderly populations.

Key words: COVID-19, elderly, clinical feature, molecular mechanism, strategy

Coronavirus disease 2019 (COVID-19) is an emerging
respiratory infectious disease caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2),
which was first identified in mid-December 2019 in
Wuhan, China. Currently, it has spread globally and been
declared a pandemic by the World Health Organization
(WHO). Up to August 18,2020, more than 767,000 deaths
and 21,500,000 confirmed positive cases have been
reported around the world. Accumulating evidence shows
that age and underlying conditions of virus contacts are
crucial factors influencing personal fate toward different
clinical severities of COVID-19, ranging from
asymptomatic, mild, and moderate to death [1, 2].
COVID-19 shows a considerably elevated mortality rate
in patients with advanced age and pre-existing
comorbidities [3]. Under the situation of global aging, the
COVID-19 pandemic creates challenges for not only
widespread public health but also biomedical and clinical
aging research [4].
Clinical features of COVID-19 in elderly patients
New coronavirus-exposed populations are generally
susceptible, but elderly people, especially those with
underlying conditions normally considered to be aging-
associated diseases (diabetes, hypertension, and
cardiovascular and cerebrovascular diseases), exhibit
increased susceptibility [5]. Moreover, the spread of
SARS-CoV-2 as well as severe acute respiratory
syndrome coronavirus (SARS-CoV) in 2003 made it clear
that these aging patients are more likely to progress to
severe disease and die more easily from these infections
than younger people [6-8].After analyzing the data for
1099 COVID-19 patients from 552 hospitals in China,
Nanshan Zhong et al. found that patients with severe

*Correspondence should be addressed to: Dr. Lanjuan Li, The First Affiliated Hospital, College of Medicine, Zhejiang University,
310003 Hangzhou, Zhejiang Province, China. E-mail: ljli@zju.edu.cn. #These authors contrinuted equally to this work.
Copyright: © 2020 Yang Y et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN: 2152-5250 1481
Yang Y., et al
disease were older than those with nonsevere disease and
that coexisting illness was more common among patients
in the severe group[9]. In the United States, 80% of deaths
have occurred in patients over the age of 65 years, and
patients aged 85 years and over have a high proportion of
severe outcomes, mirroring the experience in China [10].
According to a meta-analysis, serious aging-related
chronic diseases(associated with a pathological role of
cellular senescence), including hypertension, diabetes,
chronic obstructive pulmonary disease (COPD),
cardiovascular disease, and cerebrovascular disease, are
independent risk factors associated with COVID-19
patients [11].
Similar to those in younger patients, fever, cough and
sputum are the most common early symptoms in elderly
patients. Elderly patients are more likely to have severe
COVID-19 conditions, show lack of improvement, and
die [12]. Analyzing a total of 56 COVID-19 patients, Liu
et al. found that the pneumonia severity index (PSI) score
of elderly patients was higher than that of young and
middle-aged patients. The proportion of patients with PSI
grades IV and V was significantly higher in elderly
patients [13]. The incidence of the common fatal
presentations of COVID-19 (including ARDS, shock,
arrhythmia and acute cardiac injury) in elderly patients is
higher than in young patients [12, 14, 15]. Wang et al.
included patients with laboratory-confirmed COVID-19
and ascurtained the viral load by reverse transcriptase
quantitative PCR (RT-qPCR). The results showed that
older age was correlated with higher SARS-CoV-2 load
[16]. Studies of SARS-CoV have shown that a high initial
viral load is associated with death [17]. Accumulating
evidence indicates that the SARS-CoV-2 viral load
correlates with the risk of COVID-19 progression and
poor prognosis [18, 19]. Thus, it is conceivable that the
poor prognosis of elderly COVID-19 patients may be
related to a higher viral load. However, the underlying
mechanism requires further exploration.
Mechanism of COVID-19 in elderly patients
Senescent cells accumulate with age in vertebrates and
promote aging mainly through the senescence-associated
secretory phenotype (SASP) [20]. Data have shown that
RNA viruses, such as influenza virus, display enhanced
replication efficiency in senescent cells, which suggests
that the accumulation of senescent cells in aging and age-
related diseases may play a role in this phenomenon.
However, the response to SARS-COV-2 that occurs in
senescent cells is still poorly understood [8].
Angiotensin-converting enzyme 2 (ACE2) has been
identified as areceptor for SARS-CoV-2, which directly
interacts with COVID-19 spike(S) glycoproteins [21, 22].
During infection, the S protein is cleaved into S1 andS2
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COVID-19 in Elderly Adults
by the host transmembrane protease/serine subfamily
member 2 (TMPRSS2)and protease furin [23].S1 directly
binds to ACE2 and S2 plays a role in membrane fusion
[24]. Zhou et al. analysed the expression of ACE2,
together withTMPRSS2 and Furin by the method of
single-cell RNA profiling combined with the protein
information in different tissues. According to the rank list
of candidate cells potentially vulnerable to SARS-CoV-
2,the top targets were lung alveolar type 2 (AT2) cells and
macrophages, followed by cardiomyocytes and adrenal
gland stromal cells [25]. These findings were consistent
with prominent lung symptoms, frequent heart damage
and rare bowel symptoms. Cluster of differentiation 26
(CD26) is also recommended as a potential receptor for
SARS-COV-2 [22, 26]. Intriguingly, both ACE2 and
CD26 show associations with senescence and
immunoregulation.
ACE2, which is widely distributed in the heart,
kidneys, lungs, liver, intestine, brain and testes, is a
known crucial component of the renin-angiotensin system
(RAS)[27]. According to Khemais-Benkhiat et al., RAS
is upregulated in endothelial cells with premature and
replicative senescence [28]. It has been suggested that
differential levels of ACE2 in human organs, especially
the cardiac and pulmonary tissues of younger versus older
adults, may be responsible for the disease virulence
spectrum observed in COVID-19 patients [29]. Ziegler et
al. discovered that ACE2 was a human interferon-
stimulated gene in airway epithelial cells. SARS-CoV-2
could enhance infection through species-specific
interferon-driven upregulation of ACE2 [30]. Smith et al.
also identified ACE2 as an interferon-stimulated gene in
lung cells. They found that chronic smoke exposure and
inflammatory signaling could increase ACE2 expression
levels in the respiratory tract. Their findings suggested
that SARS-CoV-2 infections could create positive
feedback loops that increase ACE2 expression and
promote viral dissemination [31].
Interestingly, it has been previously established that
ACE2 shows a protective effect in the lungs and that
ACE2 expression in the lungs decreases during aging. The
lower ACE2 level in the lungs may contribute to the poor
prognosis of SARS in the aged group [32]. According to
previous research, following SARS-COV entry, ACE2
expression is downregulated dramatically, which leads to
a compensatory overproduction of angiotensin 2 (AngII),
therefore increasing lung vascular permeability and
aggravating lung failure [33]. A similar phenomenon is
also observed in SARS-CoV-2-infected lung tissue [34].
According to Datta et al., SARS-CoV-2infects ACE2-
expressing cells in the lung, inducing shedding of ACE2
from the cells and, thus, effectively reducing ACE2
expression levels [35]. These findings support the
proposed role of ACE2 downregulation in both the
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pathogenesis and progression into ARDS in SARS and
COVID-19 patients.
The contradictions between these research results
indicate that SARS-CoV-2 regulation of ACE2 may be
complex and dynamic. Whether the regulatory
mechanism of SARS-CoV-2 toward ACE2 differs due to
the patients’ age, underlying diseases, and stages of
infection requires further exploration.
ACE2 is enriched in the heart and plays an essential
role in the regulation of heart function [36]. Burrell et al.
indicated that ACE2 expression is increased in
myocardial infarction in humans and rats [37]. Chen et al.
performed state-of-the-art single-cell atlas analysis of the
adult human heart and revealed pericytes with high
expression levels of ACE2 as target cells of SARS-CoV-
2. Patients with coronary heart disease (CHD) showed
increased ACE2expression at the mRNA and protein
levels [38]. Patients with CHD and infected with SARS-
CoV-2 are at an elevated risk of progressing into severe
disease [11, 29]. Conversely, acute cardiac injury is
reported as one of the most common complications in
COVID-19 patients, which significantly exacerbates
disease severity [39]. This evidence suggests that
enrichment of ACE2 in the myocardium makes the heart
one of the main target organs for SARS-CoV-2 infection.
The expression level of ACE2 in cardiomyocytes is
closely related to the poor prognosis of COVID-19
patients with heart diseases and the severity of COVID-
19-induced heart injury.
Cytokine storms, namely, hypercytokinemia, a
frequent feature of severe SARS, MERS, H5N1 influenza
and H7N9 influenza, are associated with disease severity
and are a predictor of prognosis [40-42]. Accumulating
data suggest that depletion of lymphocytes, activation of
cytotoxic T-lymphocytes, neutrophils and neutrophil-
mediated cytokine storms may play key roles in COVID-
19 pathogenesis [43]. COVID-19 results in increased
levels of plasma cytokines, including interleukin-6 (IL-6),
interleukin-1β (IL-1β), interleukin-7 (IL-7), interleukin-8
(IL-8), interleukin-9 (IL-9), interleukin-10 (IL-10),
granulocyte colony stimulating factor (G-CSF),
granulocyte-macrophage colony-stimulating factor (GM-
CSF), interferon-γ (IFN-γ), tumor necrosis factor (TNF-
α) and vascular endothelial growth factor A (VEGFA).
ICU patients with COVID-19 produced higher levels of
IL-6 than those not requiring ICU care [44]. According to
a meta-analysis, mean IL-6 serum levels are2.9 times
higher in patients with severe disease than in those with
nonsevere disease [45]. HighIL-6 levels are closely
correlated with the serum SARS-CoV-2 viral load, which
further affects vital signs and the occurrence of ARDS
inCOVID-19 patients [46]. Moreover, as a mediator of
SASP, IL-6 is the main functional marker of cell aging [5,
47], and the increase in IL-6 content may correspond to
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COVID-19 in Elderly Adults
the age-dependent increase in mortality of COVID-19
patients [48].
ACE2 participates in the RAS and plays an
important role in regulating IL-6-induced inflammatory
injury through the NF-κB and STAT3 pathways [49].
Kubaet al. indicated that SARS-CoV infection could
cause a reduction of ACE2 levels on cells, followed by
increased serum AngII levels [50]. AngII is one of the key
activators of NF-κB and STAT3, which stimulates the
expression of IL-6[51]. In turn, we speculate that severe
lung inflammation induced by SARS-CoV-2 infection
may induce the dysregulation of the RAS followed by the
development of ARDS.
CD26, also known as dipeptidyl peptidase 4
(DPP4), is a serine exopeptidase that is expressed
ubiquitously in human tissues, including lung, kidney,
liver, gut, and immune cell s(including T-cells, activated
B-cells, activated natural killer cells and myeloid cells)
[52, 53]. CD26 plays multiple roles in nutrition,
metabolism, and the immune and endocrine systems.
Using mass spectrometry analysis, Kim et al. identified
CD26 as a surface protein that is expressed at significantly
higher levels in senescent cells. CD26 activity is higher in
older than in younger individuals [54]. Overly
upregulated CD26 expression and activity are associated
with diabetes, obesity and metabolic syndrome, which are
reported to influence COVID-19 severity [22, 55].
Moreover, CD26 has been identified as the
functional receptor of MERS-CoV [56, 57]. Research has
indicated that MERS-CoV is associated with higher
mortality among elderly populations with chronic
debilitating diseases including diabetes, malignancy,
pulmonary and renal diseases. MERS also appears with
greater severity and higher mortality rates in elderly
people, especially those with debilitated immune
systemsorpre-existing comorbidities [58-60].Therefore,
we suggest that similar to the case for ACE2, DPP4
upregulation may be adeterminant of COVID-19
progression and prognosis.
Large numbers of studies have demonstrated the
integral role of CD26 in T lymphocyte activation during
immunesenescence and costimulation [61]. CD26 acts as
a costimulatory agent that mediates T cell activation by
binding to the ligand adenosine deaminase [62].
Additionally, CD26 enhances lymphocyte proliferation
independent of ADA [63].
CD26 can exist in a soluble form that is considered
to be released from the membrane into the plasma, which
still retains its enzymatic activity[64]. Ikeda et al. found
that soluble CD26 enhances the binding of transcription
factors to the TNF-α and IL-6 promoters, thus increasing
TNF-α and IL-6 mRNA and protein expression in THP-
1 cells [65]. CD26 inhibitors decrease the concentration
of proinflammatory factors, such as TNF-α and IL-6 [66].
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Thus, some researchers have suggested that the activation the specific role of CD26 in COVID-19 still requires
of CD26 on T lymphocytes may partially contribute to the further exploration (Figure 1).
high expression of IL-6 in COVID-19 patients. However,

Figure1. Interaction of SARS-CoV-2 with ACE2 and CD26. To enter the host cells, SARS-CoV-2 binds to membrane-bound
ACE2 with the assistance of Furin and TMPRSS2. SARS-CoV-2 infections could create positive feedback loops that increase ACE2
expression and promote viral dissemination. On the other hand, SARS-CoV-2 infections may induce ACE2 shedding. ACE2
downregulation could lead to accumulation of Ang II, therefore inducing cytokine storm and ARDS. Activation of CD26 on T
lymphocytes may partially contribute to the high expression of IL-6 in COVID-19 patients.

Proposed clinical applications in elderly covid-19 Antiviral drugs

patients
Current evidence suggests that elderly patients with past
comorbidities or dyspnea should be closely monitored for
signs of disease progression, decompensation, and
exacerbation of illness, especially 1-2 weeks after the
onset of symptoms[10, 67]. Presently, there are no
officially approved medicines available against SARS-
CoV-2. Although the management of COVID-19 patients
is primarily supportive, specific therapies are still under
investigation. These therapies include current and
potential antiviral drugs, anti-senescence drugs,
immunosuppressive agents, steroids, mesenchymal stem
cell (MSC) transplantation, and an artificial liver system
(ALS), among others (Table 1). In the following
paragraphs, we aim to highlight the proposed therapeutic
strategies [68].
Timely antiviral therapy is highly recommended early the
course of COVID-19 patients, especially elderly patients
and patients with underlying conditions. Wu et al.
retrospectively investigated the clinical data of 280
COVID-19 cases and recommended that timely antiviral
treatment should be initiated to slow disease progression
and improve prognosis in elderly patients [2]. Previously,
oseltamivir, which could reduce the mortality of influenza
patients, and ganciclovir, which is primarily used to treat
cytomegalovirus [69], were widely used for SARS-CoV-
2 patients. However, the efficiencies of neuraminidase
inhibitors are currently being questioned, which makes
them beyond recommendation [70, 71].
Remdesivir (GS‐5734) is a monophosphoramidate
prodrug of an adenosine analog that can affect viral RNA
polymerase and reduce the production of viral RNA
[72].Remdesivir has shown a significant therapeutic

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effect in MERS‐CoV mouse models [73]. It is effective in
the EC50 range of 0.069 μM for SARS‐CoV and 0.074
μM for MERS‐CoV in tissue cultures as well as 0.77 μM
in Vero E6 cells [72, 74]. Theoretically, remdesivir is
currently the most promising drug for treating COVID-19.
According to the result of a prospective, open-label study
of remdesivir, Antinori et al. indicated that this drug could
benefit hospitalized patients with SARS-CoV-2
pneumonia, with fewer adverse events observed [75]. The
clinical trial conducted by Wang et al. in 237 patients at
ten hospitals in Hubei Province showed that, although not
statistically significant, the patients receiving remdesivir
had a faster time to clinical improvement than those
receiving placebo [76]. In the trial conducted by Beigel
and colleagues, 1063 COVID-19 patients were randomly
assigned to remdesivir or placebo. The results showed that
remdesivir could obviously shorten the recovery time in
hospitalized COVID-19 patients [77]. The authors also
emphasized that earlier remdesivir treatment was
probably more beneficial than later treatment [78].
Further explorations of the safety and efficiency of
remdesivir for COVID-19 are still ongoing.

Table 1. Potential strategies for the treatment of COVID-19.

Treatment Agent Related Target/Pathways Potential efficacy in COVID-19

Antiviral drugs Remdesivir Reduces the production of viral RNA Shortens the recovery time in COVID-19
LPV/RTV Inhibits antiretroviral protease patients
Favipiravir Targets RNA-dependent RNA polymerase Shortens the viral shedding duration in patients
Induces a shorter viral clearance time and
Arbidol Perturbs the virus membrane structure greater improvement rate in chest imaging
Shorter duration of positive RNA test
compared to those treated with LPV/RTV
Antisenescence Azithromycin Targets and removes senescent cells; Reduces airway inflammation; antifibrosis
drugs inhibits IL-6 and IL-1β expression; extends
Chloroquine; the lifespan of myofibroblasts Reduces the viral load in COVID-19 patients
hydroxychloroquine Prevents the induction and accumulation of
β-Gal; inhibits the replication of SARS- Prevents and treats the severity of COVID-19
Rapamycin CoV in vitro patients
Downregulates the IL-6 pathway; reduces
the number of senescent T-cells through the
mTOR-NLRP3-IL-1β axis
ACE2-related ACE2 activator Avoids binding of S protein of SARS-CoV- Requires scientific and clinical evidence
therapy ACE2 inhibitor 2 to ACE2 Still under debate
Human recombinant soluble Inhibits ACE2 expression Blocks SARS-CoV-2 infection; prevents lung
ACE2 Directly binds to SARS-CoV-2 in the injury
circulation
CD26 inhibitor Linagliptin Attenuates DM-induced activation of Decreases the concentration of cytokines,
NLRP3 inflammatory bodies especially TNF-α and IL-6
Immunosuppressive Tocilizumab; sarilumab; Directly targets IL-6 receptors Improves clinical outcomes in severe cases
Therapy siltuximab Halts the expression of TNF-α and IL-2; Anti-inflammatory and antiviral properties in
cyclosporine-cyclophilin A blocks the replication of coronaviruses COVID-19
complex Inhibits innate and adaptive immune Improves clinical outcomes in COVID-19
Corticosteroids responses as well as immune cells patients with ARDS
MSC / Advantages in anti-inflammation, Improves pulmonary function and symptoms
transplantation antifibrosis and injury repair of patients
Artificial liver / Attenuates the cytokine storm Reduces the mortality of severe patients
system exhibiting rapid disease progression

Abbreviations: COVID-19, coronavirus disease 2019; LPV/RTV, Lopinavir/ritonavir; IL-6, Interleukin-6; IL-1β, Interleukin-1β; β-Gal, beta-
galactosidase; SARS-CoV, severe acute respiratory syndrome coronavirus; mTOR, mammalian target of rapamycin; NLRP3, nod-like receptor family
pyrin domain-containing 3; ACE2, Angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; CD26, cluster of
differentiation 26; DM, diabetes mellitus; TNF-α, tumor necrosis factor-α; IL-2, Interleukin-2; MSC, mesenchymal stem cell.

Lopinavir/ritonavir (LPV/RTV),which acts as
antiretroviral protease inhibitor, is used as an anti-HIV
drug [79]. In India, the Central Drugs Standard Control
Organization approved the restricted public health use of
the LPV/RTV combination in symptomatic COVID-19
patients [80]. However, the efficacy of LPV/RTV for
COVID-19 is still controversial. A clinical trial in Hubei
showed that early LPV/RTV treatment could shorten the
viral shedding duration in COVID-19 patients, especially
in those of an older age [81]. Cheng et al. obtained the
exact opposite result among patients with mild pneumonia
in Taiwan [82]. According to a randomized, controlled,
open-label trial in 199 patients with severe COVID-19,
mortality at 28 days and viral clearance time were
similar in the LPV/RTV group and the standard-care
group. The results suggested that no benefit was
observed with LPV/RTV treatment [74]. Therefore, the
WHO suggested larger trials with a greater variety of
COVID-19 patients [83].

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Yang Y., et al
Favipiravir (FPV), a purine nucleic acid analog that
targets RNA-dependent RNA polymerase (RdRP), is
widely used as an oral anti-influenza drug [84]. Cai et al.
conducted a clinical trial to evaluate the safety and
efficacy of favipiravir in COVID-19 patients. A shorter
viral clearance time as well as a significantly higher
improvement rate in chest imaging was shown for the
FPV group versus the LPV/r group. In addition, fewer
adverse reactions were found in the FPV group than in
the LPV/r group [85].
Arbidol, an important anti-viral drug candidate, also
showed promising effects in COVID-19. Arbidol is a
broad-spectrum antiviral molecule that inhibits both DNA
as well as RNA viruses by altering the membrane
structure of the virus [86]. According to Zhu et al.,
patients treated with arbidol show a shorter duration of
positive RNA test compared to those treated with
LPV/RTV, while nosignificant adverse effects are
observed. The results indicated that arbidol monotherapy
is superior to LPV/RTVin COVID-19 treatment [87].
Additionally, a retrospective cohort study showed that
arbidol combined with LPV/RTV showed improved
efficacy in COVID-19 patients [88]. Another
retrospective, single-center study showed that the
combination of Lianhuaqingwen and arbidol was
effective for patients with mild symptoms within 5-7 days,
and the cure rate was 98% [89]. Moreover, arbidol is
considered to have a preventive effect. Yang et al.
suggested that prophylactic oral arbidol was associated
with a lower incidence of SARS-CoV-2 infection in
medical staff [90].Although accumulating evidence has
demonstrated the potential clinical efficiency of arbidol,
powered randomized control trials are still needed for
further confirmation [91].
Antisenescence drugs
Azithromycin and the closely related drug roxithromycin
are macrolide antibiotics that can act as senolytic drugs
that target and remove senescent cells [92].Additionally,
azithromycin is known to exert an antifibrotic effect by
significantly extending the lifespan of myofibroblast
cells. Moreover, azithromycin has been proven to reduce
airway inflammation by inhibiting IL-6 and IL-1β
expression in mouse models [93, 94]. Therefore,
azithromycin is recommended by a number of researchers
as a potential COVID-19 treatment strategy. However,
Gbinigie et al. conducted a rapid review of the current
literature. The results indicated that other than in the case
of bacterial super infection, there was no evidence
supporting the use of azithromycin for the treatment of
SARS-CoV-2 infection outside of the context of clinical
trials [95]. According to a clinical trial conducted by
Rosenberg et al., receipt of azithromycin alone could not
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COVID-19 in Elderly Adults
significantly reduce in-hospital mortality of COVID-19
patients [96].
Chloroquine (CQ) and its derivative
hydroxychloroquine (HCQ) have the ability to induce
alkalization, which functionally prevents the induction
and accumulation of beta-galactosidase (β-Gal), known as
a marker of senescence [97]. CQ and HCQ are widely
used antimalarial and antiviral drugs and have recently
received much attention as potential treatments for
COVID-19 [98].CQ was recently demonstrated as an
inhibitor ofSARS-CoV-2 in vitro, and the hydroxylated
form, HCQ, has been proven to limit the replication of
SARS-CoV-2 in vitro [99, 100]. Huang et al. found that
CQ had a slight advantage over lopinavir/ritonavir in
COVID-19 patients [101]. HCQ can also specifically
inhibit the replication of SARS-CoV by interfering with
the glycosylation of ACE2 [102]. Therefore, HCQ has
been widely suggested as a potential treatment for patients
with SARS-CoV-2 infection. A number of clinical trials
have been conducted to explore the efficacies of CQ and
HCQ. According to a small open-label nonrandomized
clinical trial, HCQ treatment was significantly associated
with viral load reduction in COVID-19 patients, and its
efficacy could be reinforced by azithromycin [103].
However, according to a newly published comparative
observational study among 181 COVID-19 patients with
documented severe acute respiratory syndrome who
required oxygen, HCQ did not show an obvious
therapeutic effect. Additionally, eight patients in the HCQ
group (10%) experienced electrocardiographic
modifications that required discontinuation of treatment
[104]. Despite the controversial results of these clinical
trials, frequent side effects of CQ and HCQ, for example,
worsening vision, nausea, digestive disorders and
potential heart failure and even death, have hindered the
wide application of these drugs [105]. Moreover, the
results of a clinical trial conducted by Rosenberg et al.,
which involved 1438 COVID-19 patients, showed that
compared with neither treatment, treatment with HCQ
alone or combined with azithromycin was not
significantly associated with differences in mortality [96].
Rapamycin is widely known as a key anti-aging drug
and prevents the progression of senescence in human cell
lines and animal models [106-108]. Rapamycin acts as an
inhibitor of protein synthesis, inhibiting cytokine
expression and viral replication [109]. In elderly patients,
especially those with CHD or reduced T-cell counts,
rapamycin can significantly reduce the expression of the
serum senescence marker IL-6 [110]. As a candidate for
potential use in COVID-19, rapamycin may prevent
progression to severe forms of COVID-19 by
downregulating the IL-6 pathway and reducing the
number of senescent T-cells through the mTOR-NLRP3-
IL-1β axis at the early stage of cytokine storms [111,
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112].Conversely, rapamycin is suggested as a novel
intervention strategy beyond vaccines to prevent severe
symptoms in COVID-19 [113]. Therefore, conducting
clinical trials for rapamycin to prevent and treat the
severity of COVID-19 patients, especially elderly
patients, is strongly recommended.
ACE2-related therapies
Some researchers have suggested that SARS-CoV-2
induces initial damage effects by downregulating ACE2
expression and blocking ACE2-mediated activity and
activating ACE2 may be much more efficacious.
Accumulating evidence has illustrated that the activation
of ACE2 could be a positive treatment method. ACE2
activators are purported to have two therapeutic effects:
avoiding the binding of the S protein of SARS-CoV-2 to
ACE2 and promoting the protective effects of different
organs, preventing lung injury and fibrosis [34, 114,
115].ACE2 activators, such as diminazene aceturate, are
recommended for application in COVID-19 patients [34].
However, due to the positive-feedback loop between
virus infection and ACE2 expression, some researchers
have suggested the use of ACE2 inhibitors to block
SARS-CoV-2 infection. Considering the role of ACE2 in
maintaining organ functioning, especially in the lungs, the
clinical application of ACE2 inhibitors in COVID-19 is
under question [116]. The findings regardingACE2 have
sparked a debate regarding the potential use of
angiotensin-converting enzyme inhibitors (ACEIs) and
AngII receptor blockers (ARBs) among elderly COVID-
19 patients in the context of the pandemic [117].
However, after reviewing published relevant animal, in
vitro and clinical studies, Chung et al. announced that the
results did not show a higher risk of infection with ACEI
or ARB use [118]. Considering the contradictory
hypotheses and lack of scientific evidence and clinical
data worldwide, the European Society of Cardiology and
the American College of Cardiology recommended the
continuation of ACEIs or ARBs for COVID-19 patients
who were already taking these medicines [119, 120].
Human recombinant soluble ACE2 (hrsACE2) is an
FDA-approved treatment, with a 2017 phase II trial for
ARDS [121]. Circulating soluble ACE2 can bind to
SARS-CoV-2 but is unable to inhibit cell infection [122].
According to Monteil et al., clinical grade hrsACE2
reduces SARS-CoV-2 recovery from Vero cells by 1,000–
5,000 times, demonstrating that hrsACE2 can not only
block SARS-CoV-2 infection but also protect against lung
injury, suggesting a possible therapeutic approach [123].
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COVID-19 in Elderly Adults
CD26 inhibitors
The clinical immune response to SARS-CoV-2 can be
divided into 2 phases: an earlier phase of elimination by
antiviral adaptive immunity and a later phase of damaged
alveolar cells triggering innate inflammation [124].
According to Chen et al., the occurrence of ARDS may be
associated with the later immune phase, and treatment to
reduce inflammation during that phase may help reduce
lung damage. CD26 inhibitors may potentially act to
regulate an overactive immune reaction and prevent
devastating lung injury [125].In a mouse model of ARDS,
which is the main cause of death in COVID-19 patients,
CD26 inhibition by sitagliptin alleviated histological
findings of lung injury by inhibiting the expression of IL-
1β, TNF-α, and IL-6[126]. Birnbaum et al. reported that
saxagliptin-mediated DPP4 inhibition could attenuate
diabetes mellitus (DM) -induced activation of nod-like
receptor family pyrin domain-containing 3 (NLRP3)
inflammatory bodies, thus reducing serum CRP, TNF-α,
IL-1β, IL-18 and IL-6 levels [127]. CD26 inhibitors,
including sitagliptin, alogliptin, vildagliptin, saxagliptin,
and linagliptin, are a class of drugs used effectively in the
treatment of type 2 diabetes, which has demonstrated
safety in elderly patients. These drugs have similar effects
by binding to essentially the same catalytic site [128].
Research has shown that the administration of linagliptin
can lead to a decrease in the concentration of
proinflammatory factors, especially TNF-α and IL-6 [66].
Moreover, mathematical modeling has shown that the
spread of MERS-CoV infection can be controlled by
inhibiting the expression of CD26, with similar efficiency
in SARS-CoV-2 infection [129]. Since the expression of
CD26 is closely related to the pathogenesis and severity
of COVID-19, CD26 inhibitors have recently been
proposed as potential drugsagainst COVID-19 [130].
However, despite laboratory verification and theoretical
feasibility, the actual efficacies of CD26 inhibitors in
COVID-19 still require verification in further clinical
trials.
Immunosuppressive agents
As we mentioned above, COVID-19 severity and
outcomes are closely related to the characteristics of the
immuneresponse and subsequent cytokine storm incited
by pathogenic T cells and inflammatory monocytes with
a high level of IL-6 secretion, which are more severe in
elderly patients [131]. Some researchers have
recommended monoclonal antibodies that target IL-
6,TNF-α and other cytokine pathways as a potential
strategy to attenuate the inflammatory storm [132].
Tocilizumab is a marketed humanized monoclonal
antibody that directly targets IL-6 receptors.
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Yang Y., et al
Accumulating clinical trials have confirmed its safety and
effectiveness in rheumatoid arthritis treatment. In a
clinical trial among 45 patients, tocilizumab exerted a
rapidly beneficial effect on fever and inflammatory
markers in COVID-19 patients [133]. According to Xu et
al., within 5 days after additional application of
tocilizumab, the percentage of lymphocytes in peripheral
blood returned to normal in 52.6% of severe COVID-19
patients, and all patients were discharged after anaverage
of 15.1 days. The results indicated that tocilizumab
could improve the clinical outcomes in severe COVID-19
patients by suppressing the immune response [131].
Recently, tocilizumab was approved for patients with
severe SARS-CoV-2 pulmonary complications by the
National Health Commission of the People’s Republic of
China. Other monoclonal antibodies specifically targeting
IL-6 pathways, such as sarilumab and siltuximab, are also
recommended for COVID-19 treatment. Clinical trials are
still needed to evaluate their efficacy and safety in
COVID-19 patients.
The cyclosporine-cyclophilin A complex, including
cyclophilin and tacrolimus, is considered to suppress
organ rejection by halting the expression of TNF-α and
IL-2 [134]. Moreover, according to Pfefferle et al.,
cyclophilin can block the replication of coronaviruses,
including SARS-CoV, human CoV-229E and CoV-NL-
63, feline CoV, among others. These results suggest that
cyclophilin is a broad-spectrum coronavirus inhibitor and
might be used for therapy in emerging coronavirus
infections [135]. Therefore, the anti-inflammatory and
antiviral properties of the cyclosporine-cyclophilin A
complex make it a potential clinical application in severe
COVID-19. However, considering the nephrotoxicity and
hepatotoxicity of cyclophilin and tacrolimus, safety issues
must be explored in COVID-19 patients, especially
elderly individuals with liver and kidney involvement.
Corticosteroids show inhibitory effects on both
innate and adaptive immune responses, as well as multiple
types of immune cells [136]. Corticosteroids were among
the first therapies tested in trials for preventing ARDS
[137]. Meduri et al. constructed a clinical trial to
investigate the efficacy of long-term corticosteroid
treatment in patients with ARDS. The results showed that
prolonged corticosteroid application could accelerate the
resolution of ARDS and decrease hospital mortality [138].
Fadel et al. conducted a single pretest, single posttest
quasi-experiment among 213 COVID-19 patients. The
results indicated that an early short course of
methylprednisolone application could reduce escalation
of care and improve clinical outcomes in patients with
moderate-to-severe COVID-19 [139]. However, clinical
management of severe SARS and MERS patients
revealed that corticosteroid therapy did not decrease
mortality; in contrast, it caused delayed viral shedding
Aging and Disease • Volume 11, Number 6, December 2020
COVID-19 in Elderly Adults
[140]. In addition, Zha et al. announced that after
analyzing the data of 31 COVID-19 patients, they found
no association between corticosteroid therapy and
outcomes in patients without ARDS [141]. The efficacy
of corticosteroids in COVID-19 patients remains
controversial. Thus, the Guideline for the Diagnosis and
Treatment of COVID-19 (7th version) recommended low-
to-moderate doses and short courses of corticosteroid
application in selected COVID-19 cases that represent
excessive immune response activation or rapid
progression of imaging changes
MSC transplantation
MSCs are nonhematopoietic stem cells derived from the
mesoderm, which can be isolated from various tissues,
such as bone marrow, adipose tissue, umbilical cord
blood, placenta, menstrual blood, dental pulp, and
amniotic fluid [142]. Accumulating evidence from
preclinical and clinical trials has demonstrated that MSCs
have great advantages in anti-inflammation, anti-fibrosis
and injury repair [143-145]. Shao et al. reported that
MSCs could strongly suppress IL-6 production, thereby
disrupting the development of cytokine storms [146].
Previously, it was demonstrated that MSC transplantation
could significantly reduce the mortality of patients with
H7N9-induced ARDS (17.6% died in the MSC group,
whereas54.5% died in the control group). Moreover, no
significant adverse effects were observed in these patients
[147]. According to Leng et al., MSC transplantation
could significantly improve pulmonary function and
symptoms of COVID-19 patients without obvious adverse
effects. Moreover, decreased TNF-α and increased IL-10
levels were detected in the MSC treatment group
compared with the control group [148]. These results
indicated that MSC-based therapy could be a potential
alternative for managing patients with severe symptoms
of COVID-19.
Artificial liver system
The artificial liver system (ALS) is widely used as an
effective support therapy in severe liver failure patients
[149]. As mentioned above, the cytokine storm is the main
motivator of COVID-19 progression and a poor
prognosis, and its severity is closely associated with
advanced age. Previously, clinical trials have
demonstrated that the plasma exchange module of ALS
exhibited high efficacy in attenuating the cytokine storm
of H7N9 infection [150]. A single-center study showed
that artificial liver plasma exchange could significantly
reduce inflammatory cytokine levels, thus reducing
mortality in critically ill patients with COVID-19 [151].
Our colleagues found that the application of ALS showed
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Yang Y., et al
excellent prognosis in the treatment of severeCOVID-19
patients presenting a cytokine storm [152]. According to
the Diagnosis and Treatment of COVID-19 (7th version)
published in China, ALS is recommended in patients who
exhibit rapid disease progression confirmed by lung
imaging and a cytokine storm.
Nutritional support in elderly people
To date, considerable evidence has demonstrated that
food and nutrients could affect immune system function.
Poor nutritional status is widely considered one of the
significant risk factors for severe COVID-19 [153]. It has
been directly highlighted that nutritional support may play
an important role in determining COVID-19 outcomes
[154]. Generally, there are nutritional deficiencies in
calcium, vitamin C, vitamin D, folate, and zinc among the
elderly population, especially among in-hospital patients
[155]. According to a study in Wuhan, the prevalence of
malnutrition is elevated in elderly patients with COVID-
19 [156]. The researchers suggested that
nutritional support should be strengthened during
treatment. Malnutrition can exacerbate the immune
system deficiency in elderly individuals, making them
susceptible to SARS-CoV-2 infection [157]. A healthy,
balanced diet can provide elderly individuals with
necessary macro- and micronutrients, prebiotics,
probiotics, and symbiotics to restore and maintain
immune cell function, thus reducing the incidence of
SARS-CoV-2 infection [153].
Problems faced by the progress and application of the
vaccine
The development of a safe and effective vaccine against
SARS-CoV-2 for nonimmune individuals is an urgent and
critical task for controlling the ongoing pandemic [68].
The developing coronavirus vaccines and drugs mainly
target the spike glycoprotein or S protein, the major
inducers of neutralizing antibodies. To date, Wei Chen et
al. conducted a dose-escalation, single-center, open-label,
nonrandomized, first-in-human trial of a recombinant
adenovirus type5-vectored COVID-19 vaccine in Wuhan,
China. The vaccine was tolerable and immunogenic 28
days after vaccination. The humoral responses against
SARS-CoV-2 peaked at day 28 after vaccination in
healthy adults, and rapid specific T-cell responses were
noted from day 14 after vaccination [158].
However, even if a successful vaccine for SARS-
CoV-2 becomes available, an individual’s immune
response must be sufficiently strong to respond to the
vaccine, and once exposure occurs, the reaction can later
confer protection against the pathogen. Thus, vaccines
cannot provide complete protection in elderly populations
Aging and Disease • Volume 11, Number 6, December 2020
COVID-19 in Elderly Adults
due to age-related declines in immune function and the
accumulation of various diseases. According to Montoet
al., influenza outbreaks still occur in elderly nursing
homes even when vaccination rates reach 80-98%
utilization [159]. Thus, the deficiency of the elderly group
could become a gap in herd immunity that relies on
vaccines. Some researchers recommended remodeling of
the senescent immune system of elderly persons by allo-
priming as a method to restore cellular immune function.
Heterologous immunity can enhance the panviral
protection upon each viral exposure, thereby providing
long-term protection. The alloantigen priming strategy
has been proposed in conjunction with viral-specific
vaccines in the elderly population [160]. However, the
efficiency requires further exploration.
Moreover, accumulating reports worldwide of some
COVID-19 patients testing positive again after initially
testing negative indicate the potential of re-infections and
short-lasting immunity against COVID-19 [161]. To et al.
firstly reported the case of COVID-19 re-
infection by a phylogenetically distinct SARS-corona-
virus-2 strain [162]. According to Ibarrondo et al.,
antibody loss in COVID-19 patients is quicker than that
reported for SARS-CoV [163]. It means that humoral
immunity against SARS-CoV-2 may not be long lasting
in human bodies. Consequently, people doubt whether the
vaccine could produce long-term immunity in the
population.
Conclusions
The COVID-19 pandemic suggests that we are facing a
historic challenge to our capacity to protect the health of
our elderly population. Protecting aging populations is
now a central question in maintaining global health and
biosecurity [4]. Lloyd-Sherlock et al. announced that due
to great barriers in access to health services and support,
older people in low-and middle-income countries are
bearing the brunt of COVID-19 [164]. An open letter
suggested that the WHO should act immediately to
redress its neglect of older people, and member states
must prioritize the needs of the elderly population in
national responses and support for low- and middle-
income countries [165].The current results of biomedical,
clinical and public health studies also highlight the need
for therapy and prevention strategies for aging COVID-19
patients. We hope that this review can provide insight
regarding the prevention and treatment of COVID-19 in
elderly populations.
1489
Yang Y., et al
Acknowledgement
This study was supported by the National Key Research
and Development Program of China (2016YFC
1101304/3) and Zhejiang Province Key Research and
Development Plan Emergency Project (No. 2020C03123-
1).
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